Parenteral agent dispensing equipment

ABSTRACT

A parenteral delivery system and a formulation chamber are disclosed for administering a beneficial agent. The parenteral delivery system comprises a drip chamber and a formulation chamber. The formulation chamber comprises a wall surrounding an internal space and it has an inlet for admitting a liquid into the formulation chamber and an outlet for letting an agent formulation leave the formulation chamber. The chamber houses an agent delivery system for releasing a beneficial agent into a liquid that enters the chamber.

CROSS REFERENCE TO RELATED APPLICATION

This application is a continuation-in-part of patent application UnitedStates Ser. No. 310,047 filed on Oct. 9, 1981, which application isincorporated herein by reference. This application is copending withpatent application United States Ser. No. 312,491 filed on Oct. 19,1981. All of these applications are assigned to the ALZA Corporation ofPalo Alto, Calif.

FIELD OF THE INVENTION

This invention pertains to parenteral dispensing equipment comprising aformulation chamber containing an agent delivery system. The inventionalso relates to a method of parenterally administering a beneficialagent using the parenteral equipment housing the delivery system.

BACKGROUND OF THE INVENTION

The parenteral administration of medical liquids is an establishedclinical practice. The liquids are administered usually intravenously,and the practice is used extensively as an integral part of the dailytreatment of medical and surgical patients. The fluids administeredparenterally, usually intravenously, include aqueous solutions ofdextrose, sodium chloride and various other therapeutically acceptableelectrolytes. The liquids or fluids commonly administered intravenouslyinclude blood, blood substitutes, and plasma substitutes. Generally, thefluids are administered from a container suspended above the patient,with the fluid flowing through a catheter hypodermic needle set to thepatient. The needle is placed in a blood vessel, usually a vein of apatient for intravenous administration. For the intraperitonealadministration of fluids, the administration set is connected to acannula transversing the abdominal wall of the patient.

The administration of fluids parenterally is a valuable and importantcomponent of patient care; moreover, the use of parenteral fluids has inrecent years expanded beyond its original role of fluid and electrolytereplacement to include serving as the vehicle for the parenteraladministration of beneficial agents, mainly those which are desirable toadminister by infusion through intravenous, intra-arterial,intraperitoneal or subcutaneous routes. For example, presently abeneficial agent, such as a drug, is administered intravenously by oneof the following procedures: temporarily halting the flow of medicalfluid and intravenously administering the drug to the patient through aninjection port in the administration set, followed by resumption ofmedical fluid into the patient; a drug is added to the fluid in thecontainer, or into a volume control chamber in series with theadministration set, and then carried by the flow of fluid to thepatient; a drug is introduced into a so-called "piggyback" containerwhich is subsequently connected by a connector, in tributary fashion, tothe primary administration set through which the medical fluid isadministered to the patient; or a drug is administered by a pump which,by one of various recognized mechanical pumping actions, establishesflow and this determines the flow of fluid containing the drug into aflow path entering the patient, for example, an indwelling venouscatheter.

While these delivery techniques are being used, they inherently possesscertain disadvantages. For example, the administration of a drug throughrepeated injections into the administration set is inconvenient andrepresents each time a potential break in sterility; the use of pumps isexpensive and sometimes inconvenient because of their size and weight;the rate of drug delivery to the patient is directly dependent on theflow of fluid with all currently practiced means of drug infusion;because of the relative chemical instability of aqueous solutions ofmany commonly used parenteral drugs, these procedures often requiresolubilization of the drug medication by the hospital pharmacist ornurse at a time, proximate to its administration. While it is currentpractice to give some drugs by brief infusion, typically of 30 minutesto two hours duration repeated three or four times a day, they do notprovide a means for careful coordination of the procedures forsolubilization and administration, and for careful regulation of theflow of drug solution during each period of infusion to insure thatinfusion is completed within the recommended time.

In view of this presentation, it is immediately apparent a critical needexists for a dependable and practicable parenteral therapeutic deliverysystem that overcomes the disadvantages associated with the systemsknown to the prior art. It is also apparent that a pressing need existsfor a parenteral delivery system that can be used clinically foradministering parenterally a beneficial agent at a controlled rate andin a beneficially effective amount to a patient over a prolonged periodof time.

DISCLOSURE OF THE INVENTION

Accordingly, a principal object of this invention is to provide aparenteral delivery system for administering a beneficial agent at acontrolled rate and in an improved manner for optimizing the care of ahost whose prognosis benefits from parenteral therapy.

Another object of the present invention is to provide a parenteraldelivery system comprising a formulation chamber housing a deliverysystem containing a beneficial agent for delivering the agent into aparenteral fluid that enters the chamber for optimizing the care of apatient on parenteral therapy.

Another object of the invention is to provide a formulation chambercontaining a drug delivery system, wherein the chamber is adapted,shaped and sized for use in a parenteral delivery system and wherein thedevice is designed for admitting a beneficial agent at a controlled rateinto a parenteral fluid admitted into the formulation chamber.

Another object of the invention is to provide an agent formulationchamber adapted for use with an intravenous delivery system whichchamber houses an agent delivery device for admitting an agent at a rateessentially controlled by the device into an intravenous fluid admittedinto the formulation chamber.

Another object of the invention is to provide an intravenous therapeuticsystem comprising a container and a drug formulation chamber that housea delivery system for delivering a drug at a rate governed by the deviceinto a medical fluid that flows from the container into the chamber andhence to a drug recipient.

Another object of the invention is to provide an intravenous deliverysystem comprising a formulation chamber housing an agent delivery systemhaving a total surface area of a high magnitude for releasing a largeamount of agent in a limited time into a limited volume to perform apreselected agent program.

Another object of the invention is to provide a formulation chamberhousing an agent delivery system comprising a high membrane surface areafor achieving high agent release rates over time.

The invention concerns both a parenteral delivery system and an agentformulation chamber. The parenteral delivery system comprises acontainer for storing a medical fluid which is also a pharmaceuticallyacceptable carrier for the agent, a drip chamber, a formulation chamber,and a conduit for conveying the medical fluid to a recipient. Theformulation chamber comprises a wall surrounding a lumen and inlet thatpermits communication with the container and an outlet that permitscommunication with the parenteral system. The formulation chamber housesa delivery system containing a beneficial agent that is released at arate controlled by the delivery system over time. The agent on itsrelease is formulated in situ with a medical fluid that enters thechamber with the agent-fluid formulation then infused into a recipient.The agent delivery system, or dosage form, stores an amount ofbeneficial agent for executing a prescribed beneficial program, and itprovides for the preprogrammed, unattended delivery of a beneficially ora therapeutically effective amount of the agent to produce a beneficialor a therapeutic result.

BRIEF DESCRIPTION OF THE DRAWINGS

In the drawings, which are not drawn to scale, but are set forth toillustrate various embodiments of the invention, the Figures are asfollows:

FIG. 1 is a perspective view showing an embodiment of the inventioncomprising a parenteral delivery system comprising a formulationchamber;

FIG. 2 is a perspective view showing another embodiment of the inventioncomprising a parenteral delivery system comprising a formulationchamber;

FIG. 3 is a perspective view of still another embodiment of theinvention comprising a parenteral delivery system for delivering abeneficial agent solution;

FIG. 4 is a view of a formulation chamber housing a delivery systemcomprising a multiplicity of tiny timed pills;

FIG. 5 is a view of a formulation chamber seen in opened sectiondepicting the chamber housing a delivery system comprising a pluralityof tiny capsules containing a beneficial agent;

FIG. 6 is a view of a formulation chamber housing a delivery systemcomprising a multiplicity of hollow fibers filled with beneficial agent;

FIG. 7 is a view of a formulation chamber housing a delivery systemcomprising a plurality of solid fiber filled with beneficial agent;

FIG. 8 is a view of a formulation chamber housing a delivery systemcomprising a drug delivery system consisting of a bioerodible polymerhousing beneficial agent.

FIG. 9 is an opened view of a formulation chamber housing a plurality ofion-exchange members with active agent ionically bonded thereto.

In the specification and the drawings, like parts in related Figures areidentified by like numbers. The terms appearing earlier in thespecification and in the description of the drawings are describedhereafter in the disclosure.

MODES FOR CARRYING OUT THE INVENTION

FIG. 1 illustrates an operative parenteral delivery system provided bythe invention and it is generally designated by the numeral 10.Parenteral system 10 comprises a container 11 formed of a flexible, or asemi-rigid, preferably transparent plastic, such as a polyolefin, orpolyvinylchloride, and it can contain a medical fluid adapted forparenteral including intravenous administration. The medical fluid willtypically be a sterile solution, such as an aqueous solution ofdextrose, a solution of dextrose in saline, saline, and an electrolytesolution. The medical fluid also is a pharmaceutical vehicle or carrierfor a beneficial agent that is to be administered to a recipient, and asa pharmaceutical carrier it is acceptable for intravenousadministration. Container 11, in the embodiment illustrated, isnon-vented, a medical fluid in the container is at atmospheric pressure,and the container collapses as it empties of medical fluid. Container 11usually is adapted to be hung neck-down from a hanger 12 by a bib orhole 13 that is connected, or it is integrally formed as part ofcontainer 11. Container 11, at its end distant from its hanging end,that is, at its neck end, has an administration port 14 adapted forreceiving an administration set.

The administration set provided by this invention is used to deliver afluid from container 11 and a beneficial agent admitted into parenteraldelivery system 10 to a patient. The administration set is sterile,pyrogenfree, and preferably disposable. The administration set comprisesthe components described hereafter, and it connects with port 14 ofcontainer 11. Port 14 can be a diaphragm in container 11, not shown, orport 14 can be a hollow connector 15 that pierces the wall of container11. Connector 15 is adapted to receive inlet end 16 of drip chamber 17,which end 16 snugly receives connector 15 and fits snugly over the mainbody forming drip chamber 17. Drip chamber 17 has another end 18 thatfits snugly over the main body of drip chamber 17. End 18 is an outletend that establishes fluid communication between dip chamber 17 and therest of parenteral system 10. Drip chamber 17 is used to trap air and itpermits adjustment of the rate of fluid flow from container 11 as theflow proceeds dropwise. Drip chamber 17 comprises a wall surrounding alumen and the drip rate is governed by adjustable clamp 19 on secondsegment tubing 20. Clamp 19 pinches the internal diameter of tubing 20to regulate flow in cooperation with drip sight chamber 17. An outlet 18of drip chamber 17 is connected to a first segment tubing 21 that fitsinto outlet 18. Tubing 21 connects in fluid communication to inlet 22 ofagent formulation chamber 23. Tubing 20 connects to outlet 24 offormulation chamber 23 and to an adapter-needle assembly 25 that isinserted into a vein and sometimes an artery of a warm-blooded animal.

Agent formulation chamber 23 is sized, shaped and adapted for use in aparenteral system, it is self-contained, self-powered, and amenable tolow cost manufacturing. Formulation chamber 23 as seen in FIG. 1comprises a wall-forming member that surrounds an internal lumen and itis capped at its ends by inlet 22 and outlet 24. Formulation chamber 23houses an agent delivery system for introducing a beneficial agent intoa medical fluid introduced in said chamber. The use of formulationchamber 23 with the delivery system housed therein does not require anyreconstitution or admixture prior to use. Formulation chamber 23 is alight weight and disposable. Inlet 22 and outlet 24 are made forreceiving tubes 21 and 20. Formulation chamber 23 is made of glass,plastic or the like, and as illustrated it is made of a transparentmaterial for illustrating its structure and a delivery system housedtherein. The agent delivery system present in formulation chamber 23includes tiny timed pills, microcapsules, fibers, and erodible deliverysystems, a presentation of said system appears later in thespecification. Agent formulation chamber 23 generally will have acapacity of from about 10 milliliters to 250 milliliters of fluid ormore, while simultaneously housing an agent delivery system. The termfluid or liquid as used herein denotes a fluid or a liquid that can beadministered parenterally including intravenously, comprisingpharmaceutically acceptable fluids that are also a pharmaceuticallyacceptable carrier for an agent, such as water, isotonic saline,Ringer's lacetate solution, and the like. The expression beneficialagent, as used herein, generically denotes any substance that on releaseby the delivery system produces a therapeutic or a beneficial result,such as a drug, a carbohydrate, an electrolyte, and/or the like. Theterm formulation, and agent formulation as presently used herein,generically indicates the beneficial agent on release by the deliverysystem is formulated, mixed, added, dissolved, suspended, carried,and/or the like in or by the fluid in a physical-chemical formacceptable for parenteral including intravenous administration. Inaddition, formulation chamber 23 can simultaneously serve as a dripchamber while housing the delivery system. In this embodiment, theformulation chamber-drip chamber is used to achieve a desired fluid driprate. For example, the formulation chamber-drip chamber can have a fastdrip rate for adults, or it can have a slower drip rate for pediatricuse. The formulation chamber-drip chamber can be made with various sizedinlets for controlling the rate of drip, or the drip can be controlledby regulating the clamp on the tubing. The formulation chamber-dripchamber can deliver, for example, from 2 to 75 drops per milliliter overfrom 1 minute to 1 hour. More preferably, the therapist can adjust therate of flow to 1 to 20 drops per minute, or for the need of thepatient. An additional disclosure pertaining to formulation chamber 23is presented later in the specification.

FIG. 2 illustrates another operative parenteral therapeutic systemgenerally designated 10 as provided by the invention. System 10 issupported in delivery position by support 30. System 10 is a vented-typesystem that requires air to operate. System 10 comprises a container 31made of glass or rigid clear plastic suitably sealed with a rubberstopper, not shown, that is held in container 31 by annular closure rim32. Container 31 contains a fluid 33 designated preferably forintravenous administration. Air enters system 10 through air inlet 34formed as part of the inlet closure 35 of drip chamber 36. A spike 37that is hollow pierces the rubber closure of container 31 and it servesas a conduit for letting air travel from air inlet 34 into container 31and as a conduit for letting fluid 33 travel from container 31 into dripchamber 36. One point 38 of spike 37 is seen in container 31, the otherpoint of spike 32, not seen, enters drip chamber 36 for conveying fluid33 from container 31 to drip chamber 36. Drip chamber 36 is ofconventional, hollow, tubular-like design consisting of a wallsurrounding an internal fluid receiving lumen and it is connected to anagent formulation chamber 39 through a first section of tube 40 insertedinto its outlet end 41 of drip chamber 36, and it also is inserted intoformulation chamber end 42 adapted for receiving tube 40. The other end43 of formulation chamber 39 is adapted for receiving a second sectionof tube 44. Formulation chamber 39 is made of glass or plastic, and itis preferably transparent. Formulation chamber 39 can have any shapeadapted for use in a parenteral delivery system including intravenousdelivery systems, and it is preferably round and its length exceeds itswidth. Ends 42 and 43 fit snugly over the wall of chamber 39 to form anair-tight, leak-proof closure for housing a delivery system thatreleases an agent for forming an agent solution in situ, in chamber 39with fluid 33 entering chamber 39 from container 31 by mixing ordissolving therein. Tubing 44 conveys solution containing agent fromchamber 39 to needle 45 for administration to a host. A regulating clamp46 is provided on tube 40 for pinching the internal diameter of tube 40for regulating the flow of fluid 33 through the system 10.

FIG. 3 illustrates another intravenous system 10 provided by thisinvention. System 10 comprises a container 50 that is a reservoir of apharmaceutically acceptable fluid 51 that is also a pharmaceuticallyacceptable carrier for a useful agent, and it has a venting tube 52which allows air to enter container 50 as medical fluid 51 is infusedinto a patient. Container 50 is closed with a stopper 49, and it has ahole for venting tube 52. Closure rim 53 around container 50 holdsstopper 49 in container 50. Container 50 is connected through a hollowspike 54 adaptor to the intravenous system for sending medical fluid 51from container 50 through system 10 to a patient. Spike 54 connects to afirst section of tubing 55 that enters formulation chamber 56 at itsinlet 57. Formulation chamber 56 comprises a wall 58 that surround aninternal space 59. Formulation chamber 56 houses in space 59 a drugdelivery system, seen in later figures, for performing a beneficialprogram. An agent on release from the delivery system is present in apharmaceutically acceptable form that can undergo dissolution, or it candisintegrate into smaller parts and dissolve in the presence of liquidthat enters opened-view formulation chamber 56 to form in chamber 56 anagent solution. A second section of tubing 60 connects outlet end 61 ofchamber 56 with inlet 62 of opened-view drip chamber 63. Tubing 60passes through a first clamp 64 used for regulating flow from container50 through formulation chamber 56 and into drip chamber 63. Drip chamber63 is as previously described, made preferably of a see through materialsuch as glass or plastic for visibly counting a measurable number ofdrops 65 that pass through said drip chamber 63 in unit time. Dripchamber 63 is seen in opened view and it comprises a wall 66 thatsurrounds an internal space 67 containing fluid 51 that enters as drops65. A second section of tubing 68 connects outlet 69 of drip chamber 63with administration needle 70. Tubing 68 passes through a regulatingclamp 71 used for regulating flow through system 10 to a patient.Regulating clamp 64 and regulating clamp 71 can be adjustedindependently or they can be adjusted together to act as a unitregulator.

FIGS. 4 through 8 depict structural embodiments of formulation chambershousing delivery systems that can be used in the parenteral deliverysystems of FIGS. 1 to 3. In FIG. 4 a formulation chamber 73 isillustrated with a section removed for depicting the inside of thechamber. The chamber is light weight, disposable, and indicated for usein patients requiring intravenous administration of a fluid containing abeneficial agent, such as an intravenously administrable drug. In FIG.4, formulation chamber 73 comprises a walled body 72 of tube shape andit has a pair of caps 74 and 75 for forming a closed chamber containingfluid and a delivery system. Caps 74 and 75 fit chamber 73 and they arepreferably made of self-sealing rubber through which a needle or ahollow spike can be inserted, or they can have an integrally formedtubular extension 76 and 77 for receiving an incoming tube. Hollowtubular member 76 and 77 are preferably round for receiving a tube thatslides into, or slides over the member. Formulation chamber 73 is madeof a material that is moisture proof, impermeable to microorganisms,ionizing ray permeable and adapted to house a delivery system and anyincoming fluids, including aqueous and non-aqueous fluids.

The delivery system depicted in formulation chamber 73 comprises amultiplicity of tiny timed pills 78 for the controlled delivery of anagent, including drug, into a fluid entering chamber 73. The tiny pillsare seen in detail, in opened section pills 79, and they comprise a coreof drug 80 surrounded by a wall 81 formed of a release rate controllingmaterial. The tiny timed pills 78 provide a high membrane surface areafor achieving high release rates of agent for forming an agent solution.The total number of tiny pills 78 in formulation chamber 73 can bevaried as an added means for regulating the amount of agent madeavailable for forming an agent solution. The materials forming wall 81can be selected from materials that release drug 80 by differentphysical-chemical mechanisms. These mechanisms include erosion,diffusion and osmosis mechanisms. Wall 81, when releasing drug byosmosis, released drug by bursting. Drug 80 in this embodiment ispresent in the form of an osmotic solute, such as a therapeuticallyacceptable salt, and it exhibits an osmotic pressure gradient acrosswall 81 against an external fluid. The membrane materials used to formwall 81 are those permeable to the passage of an external fluid andsubstantially impermeable to the passage of drug. Typical materialsinclude a member selected from the group consisting of celluloseacylate, cellulose diacylate, cellulose triacylate, cellulose acetate,cellulose triacetate, and and like. The osmotic wall can be coatedaround the drug in varying thickness by pan coating, spray-pan coating,Wurster fluid air-suspension coating and the like. The wall is formedusing organic solvents, including methylene chloride-methanol, methylenechloride-acetone, methanol-acetone, ethylene dichloride-acetone, and thelike. Osmotic wall forming materials, procedures for forming the wall,and osmotic bursting procedures are disclosed in U.S. Pat. Nos.2,799,241; 3,952,741; 4,014,334; and 4,016,880.

Wall 81 of tiny pills 78 in another embodiment can be made of a drugrelease rate controlling material. That is, drug 80 dissolves in thewall or through pores within the wall and passes through the wall orthrough said pores at a controlled rate by diffusion over time.Exemplary materials useful for forming a diffusional wall or a wall withpores include ethylene-vinyl acetate copolymer, ethyl cellulose,polyethylene, cross-linked polyvinyl pyrrolidone, vinylidenechloride-acrylonitrile copolymer, polypropylene, silicone, and the like.The wall can be applied by techniques described above, and materialssuitable for forming wall 81 are described in U.S. Pat. Nos. 3,938,515;e,948,262; and 4,014,335.

Wall 81 of tiny pills 78 can be made of bioerodible material thatbioerodes at a controlled rate and releases drug 80 to the fluid inchamber 73. Bioerodible materials useful for forming wall 81 includepolycarboxylic acid, polyesters, polyamides, polyimides, polylacticacid, polyglycolic acid, polyorthoesters, and polycarbonates. Thesepolymers and procedures for forming wall 81 are disclosed in U.S. Pat.Nos. 3,811,444; 3,867,519; 3,888,975; 3,971,367; 3,993,057; and4,138,344. The amount of drug present in a tiny timed pill generally isabout 10 ng. to 20 mg, and the number of tiny pills in a chamber isabout 10 to 1000, preferably 50 to 150. The tiny pills comprising thewall and the inner core of drug have a diameter of at least 100 microns,and in a presently preferred embodiment a diameter of at least 2000microns. The tiny pills can have one or more coatings of wall-formingmaterials thereon. Chamber 73 optionally is equipped with a support 82for the tiny pills. Support 82 can be a film having a release ratecontrolling properties and made of a polymer that releases drug fromchamber 73, support 82 can be a microporous polymeric membrane, asintered glass support, a perforated grid, and/or the like.

FIG. 5 illustrates a formulation chamber 84 comprising a wall 85surrounding a lumen 86 having an inlet 87 and an outlet 88. Chamber 84houses a plurality of tiny capsules 89 further seen in opened sectioncapsule 90. Capsules 90 comprise a wall 91 surrounding a mass of liquiddrug 92. The tiny capsules can be made by coacervation techniqueconsisting essentially of forming three immiscible phases, a liquidmanufacturing phase, a core material phase and a coating phase. Thecoating phase is deposited as a liquid on the core material andrigidized usually by thermal, cross-linking or desolvation techniques,to form tiny microcapsules. The capsules made by this technique have anaverage particle size of from several tenths of a micron to 5,000microns, and in some embodiments a larger tiny capsule can be usedherein. Particle size however, is not critical in the practice of thisinvention. Suitable techniques for preparing tiny microcapsules arereported by Bungenberg de Jong and Kass, Biochem.Z., Vol. 232, pages 338to 345, 1931; Colloid Sience, Vol. 11, "Reversible System," edited by H.R. Kruyt, 1949, Elsevier Publishing Co., Inc., New York; J. Pharm. Sci.,Vol 59, No. 10, pages 1,367 to 1,376, 1970; and Pharmaceutical Science,Remington, Vol. XIV, pages 1,676 to 1,677, 1970, Mack Publishing Co.,Easton, PA. Formulation chamber 84 also contains a film 93 that supportsthe tiny capsules and which film can also serve as a means forregulating the release of drug solution from formulation chamber 84.

FIG. 6 illustrates a formulation chamber 95 comprising a wall 96 thatsurrounds an internal lumen 97 with an inlet end 98 and an outlet end99. Chamber 95 houses a multiplicity of hollow fibers 100, with onefiber seen in opened section comprising a wall 101, that can be formedof a semipermeable polymer, a diffusional polymer, a microporouspolymer, a lamina, or a laminate of two or more lamina, surrounding alumen 102 containing drug 103. The hollow fibers provide a large exposedsurface area for concomitantly releasing a large amount of agent intothe formulation chamber. The hollow fibers can have a length of a fewmillimeters to many centimeters or longer, a diameter of a millimeter orlarger, and the chamber houses at least one hollow fiber to severalhundred or more. The hollow fibers have openings at each end, 100a and100b, can be produced from non-cellulosic polymers using melt spinningtechniques using shaped spinnerettes. Hollow fibers can also be producedby spinning an organic solvent cellulosic solution into certainregenerants, n-octanol where the solvent is dialkylacylamide, andn-hexanol where the solvent is dimethylsulfoxide. The hollow fibers canbe filled with drug by using a solution of drug injected into one openedend of the fiber, by soaking in a drug solution, and the like. Thehollow fibers can release an agent by diffusion, dialysis, osmotic,leaching and like techniques. The amount of agent released from thefibers further can be regulated by selecting the dimensions and numberof hollow fibers housed in the formulation chamber. A procedure formanufacturing hollow fibers is disclosed in U.S. Pat. No. 4,086,418.Formulation chamber 95 optionally contains a support 104 for holding thefiber which support permits the passage of drug formulation from chamber95.

FIG. 7 illustrates a formulation chamber 105, seen in opened section,and it comprises a wall 106 that surrounds a lumen 107 with an inlet 108and an outlet 109 for admitting and exiting fluid from chamber 105.Chamber 105 houses a multiplicity of fibers 110 containing drug 111,represented by dots. The fibers 110 forming the drug delivery system canbe of natural or synthetic origin, and they can have a wide variety ofstructures, such as solid, semi-solid, porous, and the like, a varietyof geometric shapes such as round, oval, square, trilobal, variouslengths and cross-sections, and the like. The fibers can functioneffectively as a reservoir by having drug dispersed therethrough.Suitable fibers can be made by conventional fabrication techniques. Forexample, fiber material and drug may be dissolved in a solvent, extrudedthrough small holes of a die and then solidified by standard meltspinning, wet spinning, or dry spinning techniques. In anotherembodiment, the fibers can be produced by pumping a melt of fiber anddrug through a spinneret. With such a method, fiber diameter may bevaried from a few tenths to a micron to a millimeter or so bydown-drawing, or by up-drawing techniques. The lumen of the chamber canhouse fibers of mixed denier. The fibers forming the reservoir can befilled, saturated, or semi-filled with drug by immersing, soaking or thelike and permitting the desired amount of drug to transfer into thefibers. Other techniques and drugs for forming fibers are disclosed inU.S. Pat. Nos. 3,228,887 and 3,921,636. The materials forming the fiberscan be polyolefins, polyamides, polyurethanes, cellulosic materials andthe like. Fiber procedures are set forth in Encyclopedia of Science andTechnology, Vol. 5, pages 263 to 276, 1971, published by McGraw HillCo., New York. Chamber 105 also contains a membrane 112 for supportingthe fibers and it can be formed of a diffusional or porous polymer forcooperating with the fibers for regulating the amount of drug solutioninfused into a patient.

FIG. 8 illustrates a formulation chamber 113 having a section of itswall 114 removed for depicting the internal space 115 as a means forhousing for a beneficial agent delivery system 116. System 116 comprisesa reservoir formed of an erodible polymer, and a section is removed 117for illustrating agent 118 dispersed therein. The erodible polymer canbe a member selected from the group including polyorthoesters,polyorthocarbonates, polyglycolic acid, polylactic acid, polyacetals,polyketals, polyamino acids, and the like. Procedures and erodiblepolymers are disclosed in U.S. Pat. No. 4,180,646; in Int. J. ofPharmaceutics, Vol. 7, pages 1 to 18, 1980; in Biodegradables andDelivery Systems for Contraception, Chapter 2, edited by E. S. E. Hafexand W. A. A. Van Os, published by G. K. Hall, Boston, 1980. Chamber 113can also have a release rate controlling polymeric film 119 such ascellulose acetate or the like, and a filter 120. Filter 120 is aconventional filter with a pore 121 having pore size of 0.1 micron to 5micron, and more preferably 0.22 micron or 0.45 micron, for removingbacterial and unwanted matter from flowing solution, thereby aiding inmaintaining a sterile solution.

FIG. 9 illustrates a formulation chamber 123 in opened-view comprising awall 124 surrounding an internal space closed at its inlet end with cap126 and at its outlet end with cap 127. Cap 126 has a tube receivingmember 128 and can 127 has a tube receiving member 129 for letting afluid into and out of formulation chamber 123. Formulation chamber 123houses an agent delivery system comprising a plurality of ion-exchangeresin particles 130 having an agent 131 ionically attracted thereto. Theresins can be particles, bead, and droplet shaped. The particles and thelike can vary in size, usually from 10 to 350 mesh. The resins can behomopolymers, copolymers, derivatives thereof, or cross-linked resins.Typical resins include ion-exchange resins such as cross-linkedstyrene-divinyl benzene and the like, having agent 131 ionically bondedthereto. Active agent 131 is released from resin 130 into fluid thatenters the formulation chamber to form in the chamber an agent solutionfor administering to a patient. Chamber 123 also can house a releaserate controlling film 132 and a filter 133 having pores 134 forpreventing bacteria and unwanted matter from leaving the formulationchamber. The ion-exchange resins are disclosed in U.S. Pat. No.4,203,440.

The parenteral systems comprising the formulation chamber can be used,in one embodiment in fluid replacement, such as administering plasma,saline or the like, and simultaneously administering a therapeuticallyeffective amount of agent, drug or prodrug therewith; in anotherembodiment as in a method of electrolyte balance replacement, such assupplying sodium, potassium, chloride ions, or the like with a drug inan active form, in an inactive form that is converted in the animal toan active form, or in a form that is made active in the drug formulationchamber and administered therewith to an animal, such as a human patientin need of electrolyte restoration and an intravenous drug; and in amethod of intravenous nutrition, such as supplying dextrose andconcomitantly administering a drug to a warm-blooded animal such as apatient in need of such therapies. The intravenous therapy system alsocan be used in the practice of verterinary medicine.

The novel and useful invention provides an apparatus and a method forthe obtainment of precise control of agent release with a parenteraldelivery system for administration to a warm-blooded animal. While therehas been described and pointed out features of the invention as appliedto presently preferred embodiments, those skilled in the art willappreciate that various modifications, changes, additions, and omissionsin the invention illustrated and described can be made without departingfrom the spirit of the invention.

I claim:
 1. A formulation chamber for use in a parenteral deliverysystem, comprising:(a) a wall surrounding an internal lumen; (b) aninlet for admitting a fluid into the chamber; (c) an outlet for lettinga fluid leave the chamber; and, (d) an erodible delivery system in thechamber, comprising:(1) a matrix formed of a parenterally-acceptablematerial that erodes in the presence of a parenteral fluid over time,and; (2) a beneficial agent dispersed in the matrix that is delivered bythe erodible delivery system into parenteral fluid that enters theformulation chamber.
 2. The formulation chamber for use in a parenteraldelivery system according to claim 1, wherein the chamber contains aseparate film that aids in controlling the rate of release of agentformulation from the chamber.
 3. The formulation chamber for use in aparenteral delivery system according to claim 1, wherein the chambercontains a separate porous film that aids in controlling the rate ofrelease of agent formulation from the chamber.
 4. The formulationchamber for use in a parenteral delivery system according to claim 1,wherein the chamber contains a perforated grid that supports erodibledelivery system in the chamber.
 5. The formulation chamber for use in aparenteral delivery system according to claim 1, wherein the parenteraldelivery system comprises a drip chamber in fluid communication with theformulation chamber.
 6. An intravenous delivery system for administeringa beneficial agent intravenously to a human, comprising:(a) a containerof a pharmaceutically acceptable liquid; (b) a drip chamber in fluidcommunication with the container for determining the rate of fluid flowthrough the intravenous system for the continuous drip administration ofliquid; and, (c) a formulation comprising:(1) a wall surrounding alumen; (2) an erodible agent delivery system in the chamber comprising amatrix formed of a polymer containing agent dispersed therein, whichmatrix erodes in the presence of a pharmaceutically acceptable liquidthat enters the formulation chamber; and, (3) wherein the formulationchamber is in fluid communication with the drip chamber such that liquidflows into the formulation chamber and forms with agent released fromthe matrix an agent formulation over time.